The invention herein is directed to new controlled release multi-layer pharmaceutical compositions containing a combination of naproxen and naproxen sodium. The first layer of the pharmaceutical composition consists of delayed release granulates of naproxen compressed together with immediate release granulates of naproxen. A layer of immediate release naproxen sodium is compressed onto the first layer of naproxen forming an adjacent layer or layers.
Naproxen, [(S)-6-methoxy-.alpha.-methyl-2-naphthaleneacetic acid, hereinafter also referred to as naproxen acid] is of the formula ##STR1##
Naproxen is widely used (in such an acid state) as an anti-inflammatory compound in the treatment of arthritis, and as an analgesic and antipyretic in the treatment of mild to moderate pain, such as dysmenorrhea or arthritis.
Naproxen has a low water solubility and a comparatively slow rate of absorption which is a disadvantage when using naproxen as an analgesic. This drawback is overcome by the use of its salt, naproxen sodium. Naproxen sodium is the sodium salt of naproxen acid. Naproxen sodium, due to its higher water solubility, has a comparatively faster rate of absorption leading to a prompt analgesic and antipyretic effect. Hence, naproxen sodium is the drug of choice in the treatment of mild to moderate pain where a prompt therapeutic effect is desired. After absorption, both naproxen and naproxen sodium exist in the circulating blood as naproxen anions.
Naproxen is available in 250 mg, 375 mg and 500 mg tablets and is generally administered in therapeutic doses of 500-1000 mg per day, while naproxen sodium is available in 275 mg and 550 mg tablets and is administered in therapeutic doses of 550-1100 mg per day. Both compounds have multiple frequencies of administration of 8-12 hours every day.
Conventional dosage forms of naproxen or naproxen sodium are administered two to three times daily to maintain therapeutic blood levels which results in a large fluctuation in peak and trough blood levels. Controlled release dosage forms for naproxen have been designed to overcome this drawback by reducing the fluctuation and maintaining the desired therapeutic blood concentration as well as reducing the frequency of drug administration.
Hsias and Kent (U.S. Pat. Nos. 4,571,333 and 4,803,079) disclose the use of controlled release naproxen formulations and disclose the use of controlled release naproxen sodium formulations. Therapeutic blood peak levels of naproxen are not achieved promptly by these formulations and take greater than 6 hours to be achieved, as indicated by the maximum concentrations (C.sub.max) disclosed therein.
Rotini and Marchi (U.S. Pat. No. 4,888,178) disclose galenic formulations made of a mixture of immediate release naproxen granulate and a controlled release naproxen granulate. Naproxen, in its acid form (naproxen acid), is used in both the immediate release granulate and the controlled release granulate.
Although the concept of using either naproxen or naproxen sodium independently in controlled release dosage forms has been demonstrated, the art available has several disadvantages. First, the relevant art demonstrates that therapeutic blood levels, as indicated by the maximum concentration (C.sub.max) are not achieved promptly to exert a fast therapeutic response. Such a delay in reaching therapeutic blood levels is unsuitable for use as an analgesic and antipyretic in the treatment of mild to moderate pain such as dysmenorrhea or arthritis, where fast onset of action is necessary to obtain pain relief.
Furthermore, utilizing naproxen sodium alone in a controlled release system disclosed in the relevant art results in failure to maintain therapeutic blood concentration for a prolonged duration of 24 hours since its higher solubility will not delay the release of the compound from the dosage form at a rate comparable to naproxen.
In addition, matrix systems described in the art are designed to remain intact, and since naproxen and naproxen sodium are known to be irritants to the gastrointestinal tract, such systems may not empty from the stomach due to its large size. The retention of such systems in the stomach may thereby cause gastric damage.
It would be desirable to provide a pharmaceutical composition that achieves a therapeutic blood level of naproxen anions promptly to exert a fast therapeutic analgesic effect, which composition also maintains the therapeutic blood concentration for a prolonged duration of 24 hours being therefore suitable for once a day administration and which does not remain intact as a matrix.